Injury caused by either trauma or disease to the nervous system is quite common and often involves axonal pathways. Although recovery from axonal injury through regeneration often occurs in the peripheral nervous system (PNS), similar injury in the central nervous system (CNS) often results in permanent deficits due to a lack of regeneration. The long-term objectives of the research proposed is to characterize cellular and molecular responses following axonal injury that underlie this dramatic difference in the capacity of the adult mammalian PNS and CNS to support axonal regeneration. One striking difference is the response of circulating monocytes. In the PNS, monocytes rapidly infiltrate degenerating nerve after a delay of a few days where they differentiate into activated macrophages that selectively target degenerating axons and myelin. In the CNS, very few if any monocytes are recruited from the circulation and the resident microglia mount a greatly reduced and delayed response. One hypothesis to be tested is that the monocyte/macrophage response in the PNS during axonal degeneration plays an important role in establishing conditions conducive to axonal regeneration. Cell surface adhesion molecules, shown in other systems to mediate the migration of monocytes across vascular endothelial cells, will be investigated in both peripheral nerves undergoing degeneration as well as along the PNS/CNS pathway of degenerating dorsal root sensory axons. Antibodies to these molecules will also be used to block the monocyte/macrophage response and thereby determine its contribution to axonal regeneration. Conversely, the effect of enhancing the monocyte/macrophage and microglial response in the CNS on regenerating dorsal root axons at the PNS/CNS interface will also be investigated. A second hypothesis to be tested is that myelin breakdown, initiated by Schwann cello is an important factor causing monocyte infiltration in the PNS. The effect of injecting a myelin breakdown product directly into the PNS and CNS will be investigated on both monocyte recruitment and the expression of cell adhesion molecules by vascular endothelial cells and monocytes/macrophages. The monocyte/macrophage response has also been implicated to play an important role in various diseases producing demyelination and/or loss of axons. A better understanding of its role during injury, repair, and disease processes affecting the nervous system will helpfully lead to new and improved clinical treatments.